A crisis in clinical research

Abstract

The clinical research pipeline is critical to ensuring continued development of novel treatments that can offer patients with cancer safe and effective options. Unfortunately, progress has slowed since the COVID-19 pandemic due to uncovered, systemic inefficiencies across critical processes. Towards initiating discussion on how to reinvigorate clinical research, the Society for Immunotherapy of Cancer (SITC) hosted a virtual summit that characterized issues and formed potential solutions. This commentary serves to highlight the crisis facing clinical research as well as stimulate field-wide discussion on how to better serve patients into the future.

Introduction

A patient with cancer in their 70s was diagnosed with chemotherapy and immune checkpoint inhibitor (ICI)-refractory non-small cell lung cancer. Without any effective treatment options, they joined a clinical trial of sotorasib, the first-in-class KRAS^G12C inhibitor, achieving an ongoing partial response for greater than 2 years. Sotorasib was subsequently approved by the US Food and Drug Administration (FDA) for patients like them. The groundbreaking development of the first drug to target a key oncogenic driver is yet another example of remarkable advances in molecular biology and medicinal chemistry, leading to the creation of novel anticancer agents. In parallel, development of ICIs and cellular therapies in the past decade have collectively improved patient outcomes across the spectrum of human malignancy, and innumerable immune modulators are currently in or will soon enter clinical trials. However, increasing inefficiencies in the activation, conduct and oversight of oncology clinical trials are slowing clinical development of potentially life-saving therapies. The inefficiencies also increase costs of clinical development and likely narrow testing of new agents and approaches in clinical trials.

The slowing of clinical research is a national crisis and is due in part to administrative and regulatory burdens, outmoded data collection and broken clinical trial business models. The severe constraints to drug development and ultimately patient access to treatment come at a time of unprecedented scientific opportunities. Accordingly, The Society for Immunotherapy of Cancer (SITC) hosted the Crisis in Clinical Research Virtual Summit to assess and address these issues (table 1). Of note, stakeholders at this summit agreed that the COVID-19 pandemic did not cause the crisis, but rather amplified existing problems within the clinical research system. We highlight key areas of concern and propose solutions to sustain clinical research.

Table 1. Potential solutions to the crisis in clinical research identified during the Society for Immunotherapy of Cancer (SITC) August 2022 virtual summit.

Standardization and centralization ofclinical research resources	Cross-institutionaldata availability	Maximizing efficiency across clinical research operations	Diversification ofclinical research sites and populations
Develop consensus on structured data inputs Standardize clinical research contracting and budgeting language Adopt standard timelines across the field for implementation of EDC automations Implement consistent EMR builds and compatibilities Incorporate and accept centralized IRBs and SRCs	Collect clinical research accrual and activation data to drive future innovation Expand on current data collection efforts Promote impartial and accepted data sharing culture across institutions and stakeholders	Embrace automation Incorporate business-like operations within clinical research workstreams Perform work in parallel toward identifying potential efficiencies/inefficiencies Reduce silo’s and streamline communications across stakeholders Develop processes that maximize personal and professional success for the available workforce	Expand access of clinical trials to underrepresented communities Increase patient education towards enhancing clinical trial acceptance Provide education to community centers towards becoming fully equipped clinical research sites

EDCelectronic data captureEMRelectronic medical recordIRBInstitutional Review BoardSRCScientific Review Committee

Not speaking to one another: clinical trial data

Accurate collection and analyses of patient data is central to drug approval. However, the processes used to transport clinical trial data from electronic medical records (EMRs) to clinical research forms (CRFs) to the FDA lag far behind many other data-intensive industries. A root cause is uneven or outright lack of standardization and harmonization of clinical trial data. Indeed, creating a clinical trial note that accurately captures an observation and allows for an efficient clinical workflow remains elusive. Even where standards are available, for example, for tumor response (Response Evaluation Criteria in Solid Tumours (RECIST)) and adverse events (Common Terminology Criteria for Adverse Events (CTCAE)), the amount and complexity of data are not easily captured in CRFs. For more structured data such as laboratory values, there are no requirements for application programming interfaces (APIs) to automatically transfer data from EMRs to CRFs, and adding to the complexity, there are many different EMR systems and equally many different CRF data systems. Broad implementation of currently standardized APIs like Fast Healthcare Interoperability Resources (FHIR) is limited because most CRFs are not created with this functionality. Third-party vendors are creating tools to automate direct EMR to CRF data transfer, but they remain limited to specific systems such as Electronic Prescribing of Controlled Substances (EPIC) and require additional costs on already strained clinical trial budgets. Expedited development and application of technology enabling direct EMR to CRF data transfer for all clinical trials, perhaps stimulated by mandates from FDA or national trial organizations such as National Cancer Insitute-National Cancer Institute's Cancer Therapy Evaluation Program (NCI-CTEP), may produce more efficient, accurate, and less costly data flow from patient to FDA.

The muddy clinical trial regulatory path

From initiation of clinical development, drug approval can take an average of 8.3 years.¹ The clinical trial pipeline is at an all-time high, driven by an increasing number of agents and scientific data generating new clinical questions. For example, there are currently almost 5000 active trials for programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) regimens, 83% of which are combination trials.² Similarly, the number of new anticancer molecules entering clinical trials exponentially increased over the years with close to 3000 new drugs in phase I development in 2022.³ The very large flux of new anticancer molecules and approaches requires an efficient clinical trials system to identify and bring to market the most effective therapies.

Prolonged time to clinical trial activation is an addressable problem slowing drug development. The FDA adheres to a 30-day decision on all new investigational new drug (IND) applications, indicating that many of the regulatory inefficiencies in trial activation may exist at the site and IRB level. A major reason for prolonged activation timelines is the increasing complexity of clinical protocols. Cancer therapeutic studies evolved over the past several decades to include more detailed eligibility criteria, intricate trial designs, inclusion of biomarkers, and complex informed consent documents. At study sites, particularly academic sites and especially relevant for investigator-initiated trials, increased scientific review, convoluted internal regulatory processes, complex budgets and contracts, and a growing number of amendments are slowing activation and impeding enrollment. The complexity of these studies and eligibility criteria also limit the utilization of community sites for trial enrollment and accrual of underrepresented minorities. While restrictive eligibility and data-intensive studies may be necessary during drug development, every requirement in a trial should be scrutinized and confirmed to be necessary for patient safety and to achieve the specific study goals.

Because many trials are conducted at multiple sites, the lack of standardization for trial activation across sites leads to massive amounts of duplicative work, while lack of cross-institutional data preclude informed decisions on how to improve activation timelines. Generally, each site conducts site specific scientific and ethical (IRB) reviews, and generates site-specific budgets, contracts, and informed consent documents, in addition to site-specific clinical order sets for the EMR. Implementation of a centralized IRB at lead sites for clinical trials may increase the efficiency and speed of trial activation. Australia has adopted such a system where if one lead site has implemented a trial, all other participating sites may also activate under Australian regulatory agency rules.⁴ Additional efficiencies could be obtained if regulatory bodies across regions such as USA, Canada, Europe, and Asia were aligned. Harmonization across regions could result in reducing drug development costs and timelines.

As a general principle, transferring responsibility for activation-related activities, for example, scientific review, IRB review, contract, informed consent, and preparation of EMR order builds from an individual trial site to a central review authority would benefit the trials system. Participation in the Cancer Centers Program, NCI-sponsored trials or Cancer Cooperative Group trials—where many of these issues are exacerbated due to their cross-institutional nature—could be contingent on accepting central documents and review, therefore limiting individual site review decisions to feasibility and competing trials.

The broken clinical trial business model

The current clinical trial business model is unsustainable and does not effectively serve patients. Staffing is central to this broken system—although the number of protocols has multiplied, the trained labor pool has not. The COVID-19 pandemic accelerated this problem like in many other industries. Most clinical trial personnel are trained on the job, with very few college or vocational degrees dedicated to regulatory sciences and clinical research that focus on training clinical research staff. There is a need to create professional pathways in colleges and nursing schools specifically for regulatory science and clinical research careers. Similar shortages exist with physicians trained to support clinical trials as well as compensation structures that allow providers to participate in research without sacrificing appropriate compensation for their effort. Overall, there is a significant need and opportunity for directed training programs in clinical research.⁵

For many trials, clinical research organizations (CROs) function as intermediaries between the sponsor and trial sites in many aspects of clinical research including site selection, data acquisition and monitoring, contract negotiations, and protocol development. Because the objectives of the sponsor and CRO may not be completely aligned, use of a CRO may lead to prolonged timelines, increased costs, increased data queries, and slower trial completion. A new model of interaction that prioritizes speed of execution as well as quality needs to be considered.

Finally, the cost of enrolling a patient has exponentially increased over the years, in effect limiting the questions that can be addressed in trials and perhaps precluding development of promising agents. A substantial part of the ballooning per patient enrollment costs can be attributed to the broken business model, trial complexity, slow activation timelines, and the inefficiencies in trial conduct and oversight.

Solving the crisis in clinical research

The pace of drug discovery is accelerating, with many promising new first-in-class drugs ready to enter the clinic or in clinical development. Certain technology advances may enhance drug development, such as improved patient selection based on biomarkers, however, the infrastructure supporting clinical trials has not kept pace with discoveries in the lab. The need to transform the current system has never been more critical. A meeting led by the FDA, NCI, international agencies, and all other stakeholders to streamline every facet of clinical research should be the highest priority for our field.